Efficacy of escitalopram for poststroke depression: a systematic review and meta-analysis

Depression is very common after stroke, causing multiple sequelae. We aimed to explore the efficacy of escitalopram for poststroke depression (PSD). PubMed, Embase, Scopus, Cochrane Central Register of Controlled Trials, Clinical trials. gov, Wan fang Data (Chinese), VIP (Chinese) and CNKI (Chinese) were retrieved from inception to May 2021. We recruited Randomized Controlled Trials (RCTs) which met the inclusion criteria in our study. The depression rating scores, the incidence of PSD, adverse events as well as functional outcomes were analyzed. 11 studies and 1374 participants were recruited in our work. The results were depicted: the reduction of depression rating scores was significant in the escitalopram groups and the standard mean difference (SMD) was − 1.25 (P < 0.001), 95% confidence interval (95% CI), − 1.82 to − 0.68; the risk ratio (RR) of the incidence of PSD was 0.52 (95% CI, 0.29 to 0.91; P = 0.007 < 0.05), which was significantly lower in the escitalopram groups; Escitalopram is safe for stroke patients; there was improvement of the motor function. However, in sensitivity analyses, the conclusions of the motor function and the incidence of drowsiness were altered. The study suggests that escitalopram has a potentially effective role compared with control groups and demonstrates escitalopram is safe. However, the results of the motor function and the incidence of drowsiness should be considered carefully and remain to be discussed in the future.

www.nature.com/scientificreports/ shows that there are no significant differences on cognitive function compared with problem-solving therapy (PST) and placebo. However, a study of escitalopram by Kim et al. 12 shows that the occurrence of moderate or severe depressive symptoms and adverse events are not statistically significant except diarrhea, ADL improvement, cognitive function, motor function and neurological defects. Two SSRI systematic reviews 13,14 enrolled RCTs of escitalopram have been found, to our knowledge, which both only included a study of Robinson et al. 11 . Recently, new RCTs of escitalopram are pouring out [15][16][17][18][19][20][21][22][23] , which were conducted in different circumstances, and the integration effects of these studies was vague. Therefore, we aimed at conducting a systematic review and meta-analysis of RCTs about escitalopram arm compared with the placebo/the blank control arm, evaluating the depression rating scores, the occurrence of depression along with depressive symptoms, the frequency of adverse events and other significant clinical outcomes.

Methods
Search strategy and study selection. 8 databases were searched (search strategy in online supplemental data), Medline via PubMed, Embase, Scopus, Cochrane Central Register of Controlled Trials, Clinical Trials.gov, CNKI (Chinese), Wan fang (Chinese), and VIP database (Chinese), from inception to May 2021. In addition, we scrutinized references of relevant papers and also contacted with authors to get the detailed data if necessary.
Inclusion criteria: ① RCTs were enrolled for participants with a clinical diagnosis of stroke; ② The experimental group was treated with escitalopram at any dose, by any mode of delivery and the control arm was included a placebo or the blank control; ③ The primary outcomes: depression rating scores, in which the Hamilton Depression Scale (HAMD) was preferred, the incidence of PSD, and adverse events including gastrointestinal side effects, sexual side events, cardiovascular adverse effects, and other adverse events. The secondary outcomes: neurological deficit scores, ADL, cognitive impairments, and motor function. For functional outcomes, we gave preference to the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index (BI), Fugl-Meyer motor scale (FM), Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA).
Exclusion criteria: ① The type of study was a non-randomized controlled study; ② The subjects were not stroke patients or no clear diagnostic criteria; ③ The experimental group was not treated with escitalopram, or the control arm was not included a placebo or the blank control, or drugs and therapies with mixed effects; ④ Outcome indicators were not required in this study; ⑤ Intervention methods were not expressed clearly and could not be verified by the authors.
Two team members exacted data of each literature independently. A third investigator was discussed with if necessary.

Quality assessment. Study quality was independently assessed by two reviewers based on the Cochrane
Collaboration's risk of bias tool including randomization, allocation concealment, blinding, incomplete outcome data, and selective reporting. An opinion was sought from a third reviewer if the first two reviewers could not reach an agreement.

Statistical analysis.
Pooled analyses were carried out at any follow-up point by RevMan 5.3 software (Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2014). Risk ratio (RR) with 95% confidence interval (CI) was described by categorical data. Standardized mean difference (SMD) with 95% CI was used for continuous outcomes. P < 0.05 was used as a cutoff for statistical significance. Statistical heterogeneity of trials was evaluated by I 224 . We used a random-effect model to calculate the pooled estimates if we observed I 2 > 50% or P < 0.10, and on the contrary, we used a fixed-effect model.
Subgroup analyses were conducted based on different rating scales, depression or not at recruitment and follow-up duration (< 3 months vs 3 ~ 6 months vs > 6 months).
In sensitivity analyses, the trails with high heterogeneity were excluded. Publication bias was assessed by a funnel plot and Egger statistical test that was carried out by Stata 12.0 and P < 0.10 was considered as statistically asymmetry 25 .
Our study was conducted according to the PRISMA 2020 guidelines. We analyzed the data about previous studies which were published early in our research, so ethical approval and patient consent were not necessary and therefore not provided.
The incidence of poststroke depression. The incidence of PSD was higher in control compared with escitalopram and with moderate heterogeneity (RR = 0.52; 95% CI, 0.29 to 0.91; 5 trials; I 2 = 72%; Fig. 4). There was no significant cardiovascular adverse effects in escitalopram groups. The RR was 1.14 (95% CI, 0.44 to 2.96; 3 trials; I 2 = 0%, P = 0.65; Fig. 6) for palpitation. For tachycardia, the RR was 1.07 (95% CI, 0.90 to 1.   Quality assessment and sensitivity analyses. The quality of studies enrolled was shown in Fig. 8. In the sensitivity analyses, studies of the low quality were eliminated 19,20,22 , and the conclusions of pooled analyses were robust, except for the motor function (SMD = 0.36; 95% CI, − 0.40 to 1.13; I 2 = 90%, P = 0.002) and the drowsiness (SMD = 4.70; 95% CI, 0.17 to 127.25; I 2 = 64%, P = 0.09). Moreover, the I 2 was decreased from 94 to 79% in the pooled analysis of the ADL. The inverted funnel plot of visual examination depression score ( Fig. 9) was symmetrical. Moreover, the Egger tests showed that the outcome of depression rating scores (t = -0.77; P = 0.478 > 0.10) was not affected by publication bias.

Discussion
The systematic review and meta-analysis give an up-to-date and detailed description of the efficacy of escitalopram for PSD, in which 11 papers and 1374 participants were enrolled. Excitingly, participants allocated to the escitalopram were more improved than the control, including depression rating scores, the incidence of PSD and motor function, but the participants enrolled in the escitalopram group did not experience more improved in aspect of the ADL, neurological function and cognitive function. Furthermore, the participants in the escitalopram groups did not suffer more adverse events compared with the control groups in our research, except for the drowsiness. However, in sensitivity analyses, the conclusions of motor function and the drowsiness were not stable, which should be considered carefully. Our research reveals escitalopram reduces effectively the depression rating scores and the incidence of PSD, which demonstrates the escitalopram is effective in the treatment and prevention of PSD. Escitalopram is safe for stroke patients in our meta-analysis. The pooled results show the participants treated with escitalopram are well tolerated for adverse events, including the gastrointestinal, cardiovascular, sexual and other adverse events but the drowsiness which only 2 trails were enrolled, however, the escitalopram groups did not experience more drowsiness in the sensitivity analyses, which is consistent with our previous meta-analysis 26 and is different from two previous meta-analyses 13,27 , due to different types of antidepressants enrolled in that researches, especially tricyclic antidepressants included in Xu et al. 27 . It is negative for the functional indexes we analyzed except for the motor function. In the sensitivity analyses, only the result of motor function is altered. The conclusions of functional indexes are not consistent with previous meta-analyses [26][27][28] , which maybe only ≤ 4 papers are enrolled in each functional index and the validity should be interpreted cautiously and proved in the future.
One of the potential weaknesses was the high heterogeneity among trials in our research, except for the incidence of PSD and adverse events. The possible reasons were analyzed. Firstly, it may be small samples of most trials we enrolled and low quality of some trails, which may lead to high risk of bias and overestimation 29 . So in the sensitivity analyses, the I 2 was decreased from 94 to 79% in the pooled analysis of the ADL. Secondly, different rating scales were used in the studies included, and one study shows the occurrence of PSD is different by different depression scales (HAM-D 17 vs. HAM-D 6 ) 30 , which proved different scales could lead to different       Fig. 16) and motor function (Supplemental Fig. 19). Thirdly, after removing the paper 16 , the I 2 was decreased from 90 to 80% in the pooled analysis of the depression rating scores, and the reason maybe the intervention duration (12 months) was obviously longer than other trails enrolled. Fourthly, after removing the trail 12 , heterogeneity (I 2 = 22%, P = 0.26) decreased significantly in the pooled analysis of cognitive function, which maybe the weight of the trail was too large and the studies enrolled were too few. The main problems of the serious cognitive impairment, aphasia, and the severe stroke about the participants were excluded in the studies recruited, therefore we could not know whether those patients could be treated with escitalopram, which was also a limitation of our research. Another limitation was that the studies enrolled were too few in some pooled analyses and related original studies should be conducted to clarify and testify the results.
The strengths also existed in our study. An extensive search was conducted, including online papers, references and unpublished trials, as well as a fairly wide range of important clinical results. Additionally, sufficient sensitivity analyses and enough subgroup analyses were performed to ensure the reliability and robustness of the results. In the future, it should be necessary to develop more detailed and rigorous basic experiments on mechanisms and clinical trials to make a better choice for clinicians and patients.

Conclusions
Taken together, our findings prompt escitalopram is safe and effective for PSD. However, the pooled analyses of the motor function and the incidence of drowsiness should be explained cautiously. Moreover, limitations and inspirations are provided for further researches in our study. Therefore, more multicenter, larger sample, more rigorous and more result indexes designed RCTs are needed to evaluate the protective role of escitalopram on PSD. License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.